1. Field of the Disclosure
The disclosure relates generally to selective esterification. More particularly, the disclosure relates to selective esterification of a carboxylic acid functional group in the presence of phenolic functional groups.
2. Brief Description of Related Technology
The honeybee hive product propolis is a folk medicine employed for treating various ailments. Many important pharmaceutical properties have been ascribed to propolis, including anti-inflammatory, antiviral, immunostimulatory, and carcinostatic activities. See, for example, Kujmgiev et al., Pharmazie, vol. 48, p. 785 (1993); Focht et al., Arzneim.-Forsch., vol. 43, p. 921 (1993); and Khayyal et al., Drugs Under Exp. Clin. Res., vol. 19, p. 197 (1993). Propolis extracts have provided an active component identified as caffeic acid phenethyl ester (CAPE), which is a carboxylic acid ester with two free phenolic hydroxyl groups. An individual study on CAPE has shown that it inhibits growth of prostate cancer in cell cultures. Differential cytotoxicity has been observed in normal rat/human versus transformed rat/human melanoma and breast carcinoma cell lines in the presence of CAPE. See Grunberger et al., Experientia, vol. 44, p. 230 (1988).
Nakanishit et al., U.S. Pat. No. 5,008,441 (Apr. 16, 1991), Burke et al., J. Med. Chem., vol. 38, p. 4171 (1995); and Stanwell et al. U.S. Pat. No. 5,610,185 (Mar. 11, 1997) describe the esterification of caffeic acid with phenethyl alcohol by refluxing the two reagents in the presence of p-toluenesulfonic acid in benzene. The product CAPE was obtained in about 40% yield after chromatography.
Hashimoto et al., Z. Naturforsch. vol. 43c, p. 470 (1988) and Son et al., Chem. Pharm. Bull. vol. 49(2) p. 236 (2001) describe the sodium salt of caffeic acid with phenethyl bromide in hexamethylphosphoramide (HMPA) to synthesize CAPE. Yields up to 70% were reported, although HMPA is reasonably anticipated to be a human carcinogen and once again a chromatography step is required for the purification.
Dicyclohexylcarbodiimide (DCC) is another reagent which has been used for esterification of caffeic acid with alcohol under mild conditions. See Chen et al., Cancer Letters, vol. 108, p. 211 (1996). However, this process also required chromatographic purification, and resulted in only about 38% yield.